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A Mitochondrial Defect in the Ion Channel, VDAC3, Alters ENaC Activity Via ROS
Author(s) -
Linck Valerie A,
Zhou Li,
Zai YuJia,
GalarzaPaez Laura,
Li Linda Wenyi,
Thai Tiffany L,
Ma HePing,
Eaton Douglas Charles
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.1005.6
Subject(s) - mitochondrion , superoxide , chemistry , reactive oxygen species , knockout mouse , microbiology and biotechnology , epithelial sodium channel , medicine , endocrinology , sodium , biochemistry , biology , enzyme , receptor , organic chemistry
It has been suggested that voltage‐dependent anion channels (VDACs) control the release of superoxide from mitochondria. We have shown that reactive oxygen species like superoxide (O 2 − ) and hydrogen peroxide (H 2 O 2 ) stimulate epithelial sodium channels (ENaC) in sodium‐transporting epithelial tissue including cortical collecting duct (CCD) principal cells. Therefore, VDACs could regulate ENaC by modulating cytosolic ROS levels. Our patch‐clamp data show that there was a significant difference in ENaC single‐channel activity between wild‐type (WT) and VDAC3 knockout mice kept on high salt (NaCl) diet for two weeks, but not on normal diet. Western blots show that a high salt diet significantly increases the expression of cleaved g‐ENaC in VDAC3 knockout mice, but not in WT mice. Consistent with this observation, systolic blood pressure was significantly increased in VDAC3 knockout mice but not in WT mice on a high salt diet for two weeks. Electron microscopy shows that a significant morphological change occurrs in the CCD cells of VDAC3 knockout mice on a high salt diet compared to WT mice which may be caused by superoxide overload in the mitochondria. These data suggest that deletion of VDAC3 sensitizes ENaC to high salt challenge and promotes salt‐sensitive hypertension. This is presumably due to ROS release in close proximity to ENaC in the apical membrane since mitochondria are concentrated in a band 1 to 2 microns below the apical membrane. Mitochondrial superoxide would be trapped in the mitochondria of VDAC3 knockout mice, but it can be degraded by mitochondrial superoxide dismutase to produce H 2 O 2 which is known to freely move across the outer membrane of mitochondria into the cytosol. Therefore, the activation of ENaC could be a direct effect of H 2 O 2 on ENaC. Alternatively, recent studies have shown that H 2 O 2 stimulates ENaC‐targeted protease activity, so H 2 O 2 could also promote ENaC cleavage to increase activity. However, the specific underlying mechanism remains to be determined. Support or Funding Information Supported by NIH R25‐DK101390 to VAL and R01‐DK100582 to HPM